Models animals per a l'estudi de la diabetis

La diabetis mellitus (DM) s'origina per mancança dels efectes de la insulina, bé perquè el pàncrees és incapaç de produir-ne, bé perquè els seus òrgans diana no responen adequadament, o per una combinació d'ambdues situacions, amb l'aparició d'hiperglucèmia, poliúria i polidípsia. En absència total de la insulina (DM tipus 1) hi ha metabolisme accelerat de proteïna muscular i greix, que pot acabar en cetoacidosi metabòlica i mort. Amb activitat insulínica residual (DM tipus 2), la malaltia es cronifica, amb obesitat, micro i macroangiopaties, i les seves manifestacions clíniques (insuficiència renal, alteracions retinals, neuropaties, infart de miocardi, etc.). La DM és un problema sanitari de primer ordre i, en ser una malaltia complexa, en la qual intervenen factors genètics i adquirits, no hi ha un model animal perfecte per estudiar-la que reprodueixi totes les característiques de la malaltia humana. La majoria de models utilitzen rosegadors, per una sèrie d'avantatges: petita grandària, facilitat d'obtenció, ràpid recanvi generacional i facilitat de manipulació genètica. En aquesta revisió parlarem de models induïts, en els quals reproduïm la malaltia mitjançant una manipulació determinada, models espontanis, consistents en soques d'animals que s'han seleccionat genèticament al llarg de successives generacions per tal que manifestin la malaltia, i models obtinguts per modificació genètica.Animal experimental models for the study of diabetes. Diabetes mellitus (DM) originates from a lack of insulin effects, due to a deficit of pancreatic production, or to an inadequate response of target organs, or a combination of both situations, ensuing hyperglycaemia, polyuria and polydipsia. When insulin is totally absent (Type 1 DM), there is an increased metabolism of muscular protein and fat, ending in metabolic ketoacidosis and death. With a residual insulin activity (Type 2 DM), diabetes becomes chronic, with obesity, micro- and macroangiopathies and their corresponding clinical manifestations (renal failure, retinal alterations, neuropathies, myocardial infarct, etc.). DM is a serious health problem and, as it is a complex illness, in which participate genetic and acquired factors, there is not a single perfect animal model for its study, able to reproduce all the characteristics of the human malady. The great majority of models use rodents, given their advantages: small size, easy access, fast reproduction rate, and a feasible genetic manipulation. We will discuss about induced models, in which the illness is reproduced by means of a specific manipulation, spontaneous models, comprised by animal breeds genetically selected along successive generations in order to them to develop the malady, and genetically engineered models

Simple sugar intake and hepatocellular carcinoma: epidemiological and mechanistic insight

Sugar intake has dramatically increased during the last few decades. Specifically, there has been a clear trend towards higher consumption of fructose and high fructose corn syrup, which are the most common added sugars in processed food, soft drinks and other sweetened beverages. Although still controversial, this rising trend in simple sugar consumption has been positively associated with weight gain and obesity, insulin resistance and type 2 diabetes mellitus and non-alcoholic fatty liver disease. Interestingly, all of these metabolic alterations have also been related to the development of hepatocellular carcinoma. The purpose of this review is to discuss the evidence coming from epidemiological studies and data from animal models relating the consumption of simple sugars, and specifically fructose, with an increased risk of hepatocellular carcinoma and to gain insight into the putative molecular mechanisms involved

Models animals per a l'estudi de la diabetis

La diabetis mellitus (DM) s'origina per mancança dels efectes de la insulina, bé perquè el pàncrees és incapaç de produir-ne, bé perquè els seus òrgans diana no responen adequadament, o per una combinació d'ambdues situacions, amb l'aparició d'hiperglucèmia, poliúria i polidípsia. En absència total de la insulina (DM tipus 1) hi ha metabolisme accelerat de proteïna muscular i greix, que pot acabar en cetoacidosi metabòlica i mort. Amb activitat insulínica residual (DM tipus 2), la malaltia es cronifica, amb obesitat, micro i macroangiopaties, i les seves manifestacions clíniques (insuficiència renal, alteracions retinals, neuropaties, infart de miocardi, etc.). La DM és un problema sanitari de primer ordre i, en ser una malaltia complexa, en la qual intervenen factors genètics i adquirits, no hi ha un model animal perfecte per estudiar-la que reprodueixi totes les característiques de la malaltia humana. La majoria de models utilitzen rosegadors, per una sèrie d'avantatges: petita grandària, facilitat d'obtenció, ràpid recanvi generacional i facilitat de manipulació genètica. En aquesta revisió parlarem de models induïts, en els quals reproduïm la malaltia mitjançant una manipulació determinada, models espontanis, consistents en soques d'animals que s'han seleccionat genèticament al llarg de successives generacions per tal que manifestin la malaltia, i models obtinguts per modificació genètica

mTOR is a Key Protein Involved in the Metabolic Effects of Simple Sugars

One of the most important threats to global human health is the increasing incidences of metabolic pathologies (including obesity, type 2 diabetes and non-alcoholic fatty liver disease), which is paralleled by increasing consumptions of hypercaloric diets enriched in simple sugars. The challenge is to identify the metabolic pathways affected by the excessive consumption of these dietary components when they are consumed in excess, to unravel the molecular mechanisms leading to metabolic pathologies and identify novel therapeutic targets to manage them. Mechanistic (mammalian) target of rapamycin (mTOR) has emerged as one of the key molecular nodes that integrate extracellular signals, such as energy status and nutrient availability, to trigger cell responses that could lead to the above-mentioned diseases through the regulation of lipid and glucose metabolism. By activating mTOR signalling, excessive consumption of simple sugars (such as fructose and glucose), could modulate hepatic gluconeogenesis, lipogenesis and fatty acid uptake and catabolism and thus lipid deposition in the liver. In the present review we will discuss some of the most recent studies showing the central role of mTOR in the metabolic effects of excessive simple sugar consumption

Fructose effects on human health: Molecular insights from experimental models

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/63704Global changes in dietary habits in the last decades caused an increase of added sugar consumption all over the world, which has been linked to the increasing prevalence of obesity, dyslipidemia, insulin resistance and cardiovascular disease. Fructose is widely used as a sweetener in the food and beverage industry, either as an integrant of the sucrose molecule or as a component of high fructose corn syrups. The consumption of fructose in beverages is especially dangerous, as the process of energy compensation by reduction in the ingestion of other foods does not work equally well with liquid than solid foods. Besides, fructose is the carbohydrate with the highest ability to induce hypertriglyceridemia, due to a marked increase in lipogenesis compared with glucose. In this review we will discuss some of the most recent studies performed in animal models and in humans to investigate the effects of excessive fructose consumption

The addition of liguid fructose to a Western-type diet in LDL-R-/- mice induces liver inflammation and fibrogenesis markers without disrupting insulin receptor signalling after an insulin challenge

A high consumption of fat and simple sugars, especially fructose, has been related to the development of insulin resistance, but the mechanisms involved in the effects of these nutrients are not fully understood. This study investigates the effects of a Western-type diet and liquid fructose supplementation, alone and combined, on insulin signalling and inflammation in low-density lipoprotein (LDL) receptor-deficient mice (LDL-R−/−). LDL-R−/− mice were fed chow or Western diet ±15% fructose solution for 12 weeks. Plasma glucose and insulin, and the expression of genes related to inflammation in the liver and visceral white adipose tissue (vWAT), were analysed. V-akt murine thymoma viral oncogene homolog-2 (Akt) activation was measured in the liver of the mice after a single injection of saline or insulin. None of the dietary interventions caused inflammation in vWAT, whereas the Western diet induced hepatic inflammation, which was further enhanced by liquid fructose, leading also to a significant increase in fibrogenesis markers. However, there was no change in plasma glucose or insulin, or insulin-induced Akt phosphorylation. In conclusion, hepatic inflammation and fibrogenesis markers induced by a Western diet supplemented with liquid fructose in LDL-R−/− mice are not associated with a significant impairment of hepatic insulin signalling

Liquid fructose downregulates SIRT1 expression and activity and impairs the oxidation of fatty acids in rat and human liver cells

Fructose ingestion is associated with the production of hepatic steatosis and hypertriglyceridemia. For fructose to attain these effects in rats, simultaneous induction of fatty acid synthesis and inhibition of fatty acid oxidation is required. We aimed to determine the mechanism involved in the inhibition of fatty acid oxidation by fructose and whether this effect occurs also in human liver cells. Female rats were supplemented or not with liquid fructose (10% w/v) for 7 or 14 days; rat (FaO) and human (HepG2) hepatoma cells, and human hepatocytes were incubated with fructose 25 mM for 24 h. The expression and activity of the enzymes and transcription factors relating to fatty acid β-oxidation were evaluated. Fructose inhibited the activity of fatty acid β-oxidation only in livers of 14-day fructose-supplemented rats, as well as the expression and activity of peroxisome proliferator activated receptor α (PPARα). Similar results were observed in FaO and HepG2 cells and human hepatocytes. PPARα downregulation was not due to an osmotic effect or to an increase in protein-phosphatase 2A activity caused by fructose. Rather, it was related to increased content in liver of inactive and acetylated peroxisome proliferator activated receptor gamma coactivator 1α, due to a reduction in sirtuin 1 expression and activity. In conclusion, fructose inhibits liver fatty acid oxidation by reducing PPARα expression and activity, both in rat and human liver cells, by a mechanism involving sirtuin 1 down-regulation

PPARa activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats

Background & Aims: Peroxisome proliferator-activated receptor a (PPARa) is a transcription factor activated by ligands that regulates genes related to vascular tone, oxidative stress, and fibrogenesis, pathways implicated in the development of cirrhosis and portal hypertension. This study aims at evaluating the effects of PPARa activation with fenofibrate on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4-cirrhotic rats. Methods: Mean arterial pressure (MAP), portal pressure (PP), and portal blood flow (PBF) were measured in cirrhotic rats treated with oral fenofibrate (25 mg/kg/day, n = 10) or its vehicle (n = 12) for 7 days. The liver was then perfused and dose-relaxation curves to acetylcholine (Ach) were performed. We also evaluated Sirius Red staining of liver sections, collagen-I mRNA expression, and smooth muscle actin (a-SMA) protein expression, cyclo-oxygenase-1 (COX-1) protein expression, and cGMP levels in liver homogenates, and TXB2 production in perfusates. Nitric oxide (NO) bioavailability and eNOS activation were measured in hepatic endothelial cells (HEC) isolated from cirrhotic rat livers. Results: CCl4 cirrhotic rats treated with fenofibrate had a significantly lower PP (29%) and higher MAP than those treated with vehicle. These effects were associated with a significant reduction in hepatic fibrosis and improved vasodilatory response to acetylcholine. Moreover, a reduction in COX-1 expression and TXB2 production in rats receiving fenofibrate and a significant increase in NO bioavailability in HEC with fenofibrate were observed. Conclusions: PPARa activation markedly reduced PP and liver fibrosis and improved hepatic endothelial dysfunction in cirrhotic rats, suggesting it may represent a new therapeutic strategy for portal hypertension in cirrhosis

Adipose Tissue Protects against Hepatic Steatosis in Male Rats Fed a High-Fat Diet plus Liquid Fructose: Sex-Related Differences

Non-alcoholic fatty liver disease is a sexual dimorphic disease, with adipose tissue playing an essential role. Our previous work showed that female rats fed a high-fat high-fructose diet devoid of cholesterol (HFHFr) developed simple hepatic steatosis dissociated from obesity. This study assessed the impact of the HFHFr diet on the male rat metabolism compared with data obtained for female rats. A total of 16 Sprague Dawley (SD) male rats were fed either a control (standard rodent chow and water) or HFHFr (high-fat diet devoid of cholesterol, plus 10% fructose in drinking water) diet for 3 months. Unlike female rats, and despite similar increases in energy consumption, HFHFr males showed increased adiposity and hyperleptinemia. The expression of hormone-sensitive lipase in the subcutaneous white adipose tissue was enhanced, leading to high free fatty acid and glycerol serum levels. HFHFr males presented hypertriglyceridemia, but not hepatic steatosis, partially due to enhanced liver PPARα-related fatty acid β-oxidation and the VLDL-promoting effect of leptin. In conclusion, the SD rats showed a sex-related dimorphic response to the HFHFr diet. Contrary to previous results for HFHFr female rats, the male rats were able to expand the adipose tissue, increase fatty acid catabolism, or export it as VLDL, avoiding liver lipid deposition. Keywords: adipose tissue; fructose; high-fat diet; leptin; non-esterified fatty acids

Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues

Human studies support the relationship between high intake of fructose-sweetened beverages and type 2 diabetes, but there is a debate on whether this effect is fructose-specific or it is merely associated to an excessive caloric intake. Here we investigate the effects of 2 months' supplementation to female rats of equicaloric 10% w/v fructose or glucose solutions on insulin sensitivity in target tissues. Fructose supplementation caused hepatic deposition of triglycerides and changed the fatty acid profile of this fraction, with an increase in monounsaturated and a decrease in polyunsaturated species, but did not cause inflammation and oxidative stress. Fructose but not glucose-supplemented rats displayed an abnormal glucose tolerance test, and did not show increased phosphorylation of V-akt murine thymoma viral oncogene homolog-2 (Akt) in white adipose tissue and liver after insulin administration. In skeletal muscle, phosphorylation of Akt and of Akt substrate of 160 kDA (AS160) was not impaired but the expression of the glucose transporter type 4 (GLUT4) in the plasma membrane was reduced only in fructose-fed rats. In conclusion, fructose but not glucose supplementation causes fatty liver without inflammation and oxidative stress and impairs insulin signaling in the three major insulin-responsive tissues independently from the increase in energy intake